Hepatoid adenocarcinoma of the lung: A case report

Abstract

BACKGROUND

Hepatoid adenocarcinoma of the lung (HAL) is a rare type of non-small cell lung cancer (NSCLC), histologically similar to hepatocellular carcinoma. HAL has high malignancy and poor prognosis, and a better treatment plan needs further study.

CASE SUMMARY

In order to deeply understand the occurrence and development of HAL, here we report a case of HAL with extensive metastasis of alpha fetoprotein negative KRAS A146T mutation. The patient refused chemotherapy and received one course of treatment (immune checkpoint inhibitors), and died three months later due to progressive disease.

CONCLUSION

HAL is a special type of NSCLC. The surgical treatment of HAL in the limited stage can achieve long-term survival, but most of them were in the advanced stage when they were found, and the prognosis was poor, which requires multidisciplinary comprehensive treatment.

Key Words: Hepatoid adenocarcinoma, Histopathological characteristics, Non-small cell lung cancer, Hepatoid adenocarcinoma of the lung, Case report

Core Tip: Hepatoid adenocarcinoma of the lung is a special type of non-small cell lung cancer, which is mainly seen in men who smoke heavily. It usually occurs in the upper lobes of both lungs, showing huge masses.

INTRODUCTION

Hepatoid adenocarcinoma (HAC) refers to adenocarcinoma that occurs in organs or tissues outside the liver with hepatocyte like differentiation and similar morphological characteristics to hepatocellular carcinoma, most of which occur in rectum, pancreas, gallbladder, kidney, lung and other organs[1]. Hepatoid adenocarcinoma of the lung (HAL) is a HAC subtype with a short survival period, which is rare clinically, and the expression of alpha fetoprotein (AFP) is uncertain[2]. Although computed tomography (CT) images can diagnose HAL to a certain extent, morphological and immunohistochemical evidence is still needed to finally diagnose HAL[3]. As this kind of disease is rare, most patients are diagnosed in late stage, and there is no standard treatment plan at present[4]. Some scholars also believe that the treatment of HAL adopts the commonly used treatment strategies of non-small cell lung cancer (NSCLC), including chemotherapy, immunotherapy, etc., but the overall prognosis of HAL is poor[5].

CASE PRESENTATION

Chief complaints

He was admitted to the hospital for 5 days because of right chest pain, and the weight had dropped by 5 kg in the last month.

History of present illness

Right chest pain, and the weight had dropped by 5 kg in the last month.

History of past illness

The patient was 76 years old, male, and had been smoking heavily for 50 years (360 pack years).

Personal and family history

No specific personal and family history.

Physical examination

Percutaneous lung biopsy showed adenocarcinoma, the immunohistochemical results were shown in Table 1. Combined with positron emission tomography (PET)/CT imaging examination, hematoxylin-eosin staining morphology and immunohistochemical examination of tumor cells (Figures 1 and 2), the patient was diagnosed as primary HAL. According to the eighth edition of The American Joint Committee on Cancer cancer staging manual, the patient was staged as cT4N2M1c IV B.

Figure 1 Morphological examination of tumor cells stained with hematoxylin-eosin. A: The cancer cells were arranged in a nest (hematoxylin-eosin, HE 200 ×); B Cancer cells are arranged in glandular tubes (HE 200 ×).

Figure 2 Immunohistochemical examination of tumor cells stained with hematoxylin-eosin. A: Immunohistochemistry showed CK7 positive (hematoxylin-eosin, HE 100 ×); B: Immunohistochemistry showed CK18 positive (HE 100 ×); C: Immunohistochemistry showed that heppar-1 was positive (HE 100 ×); D: Immunohistochemistry showed carcinoembryonic antigen positive (HE 100 ×); E: Immunohistochemistry showed Ki67 (60% +) (HE 100 ×); F: Immunohistochemistry showed that alpha fetoprotein was negative (HE 100 ×).

Table 1 The patient's immunohistochemical results.

Immunohistochemical stain	Positive	Negative
CK	+
CK7	+
CK18	+
CK19	+
Heppar-1	+
CDX2	+
Ki67	60%, +
MLH1	+
MSH2	+
MSH6	+
PMS2	+
CEA	+
Napsin		-
P63		-
TTF1		-
P40		-
AFP		-
CD34		-
Glypican-3		-
Villin		-
CK20		-
Muc2	-

MLH1: MutL homolog 1; MSH2: MutS homolog 2; MSH6: MutS homolog 6; PMS2: PMS1 homolog 2, mismatch repair system component; CEA: Carcinoembryonic antigen; TTF1: Transcription termination factor 1; AFP: Alpha-fetoprotein; CK: Cytokeratin.

Laboratory examinations

In order to formulate a standardized treatment plan, we used Next Generation Sequencing (NGS) to detect 8 genes (EGFR, KRAS, ALK, ROS1, BRAF, NTRK1/2/3, MET, RET, ERBB2) recommended by Non-Small Cell Lung Cancer, Version 4.2022, National Comprehensive Cancer Network (NCCN) guidelines in tissues, and found KRAS A146T mutation, TPS = 2%, CPS = 2, and MSI is MSS type. Because there was no effective drug for KRAS A146T mutation, we suggested that patients receive chemotherapy combined with immune checkpoint inhibitors (ICIs). The patient refused chemotherapy and received one course of ICIs treatment, and the patient died 3 months later.

Imaging examinations

PET/CT examination confirmed that: Right central lung tumor (51 mm × 36.7 mm), middle lobe tumor of right lung (71 mm × 47 mm) with mediastinal lymph node metastasis and occipital bone metastasis (31 mm × 20 mm). Osteolytic bone destruction area can be seen locally in C3 spinous process, right attachment of C4 vertebral body, thoracic 1, 3, 9 vertebral body, lumbar 2, 4 vertebral body, sacral 1 vertebral body, left iliac bone, right ribs 2, 8, left ribs 4, 6 and right femoral head, and obvious soft tissue mass formation can be seen in some lesions. The size of metastatic tumor in the right second rib was 56.0 mm × 46.0 mm. The left adrenal gland metastasized, and no malignant tumor was found in the liver (Figure 3).

Figure 3 Positron emission tomography/computed tomography. A-F: Positron emission tomography/computed tomography showed huge hypermetabolic tumors in the upper and middle lobes of the right lung, and extensive bone metastasis in the occipital, rib, spine and pelvis.

FINAL DIAGNOSIS

The patient was diagnosed as primary HAL.

TREATMENT

Because there was no effective drug for KRAS A146T mutation, we suggested that patients receive chemotherapy combined with ICIs.

OUTCOME AND FOLLOW-UP

The patient refused chemotherapy and received one course of ICIs treatment, and the patient died 3 months later.

DISCUSSION

Hepatoid adenocarcinoma is a rare extrahepatic tumor. Its morphological characteristics are similar to those of hepatocellular carcinoma[6]. About 5% of the primary sites are in the lungs[7]. According to the literature, 63% of hepatoid adenocarcinoma originated from stomach, and other sources include ovary (10%), lung (5%), gallbladder (4%), pancreas (4%) and uterus (4%)[8]. Lung is one of the least common sites of origin for hepatoid adenocarcinoma. Grossman's research HAL morphologically mimics Hepatocellular Carcinoma, Immunohistochemical stains-CK7, CK19, HEA 125, MOC31, EpCAM positive[9]. Zhuansun et al[10] analyzed 42 cases of HAL, the median age was 58.5 years. 85.7% patients were male 61.9%patients had a history of smoking, the median amount of smoking was 40 pack years. The most common site of the primary tumor was the right upper lobe (52.3%) and the left upper lobe (23.8%). Fifty percent patients had pre-treatment serum AFP increased, 76.2% (III, IV) in the progressive stage, medium overall survival of 14 months. Many characteristics are similar to those of Grossman[9].

Ishikura et al[2] first proposed the concept of hepatoid adenocarcinoma of lung. They studied five cases of primary purple adenocarcinoma with AFP expression. They adopted two criteria for diagnosis: Typical acinar or papillary adenocarcinoma and a component of carcinoma that resembles hepatocellular carcinoma and produces AFP. Kishimoto et al[11] reports the microscopic analysis of the surgical specimen revealed a large cell neuroendocrine carcinoma with occasional hepatoid foci. Haninger et al's research found that an immunohistochemical panel that includes a variety of cyclokeratins, monoclonal CEA and EpCAM markers (HEA125 and MOC31) facilitates distinction of hepatoid adenocarcinoma of lung from hepatocellular carcinoma metastatic to lung, especially when correlated with clinical and radiologic findings[12]. Haninger et al[12] propose modification of Ishikura’s diagnostic criteria1 for hepatoid adenocarcinoma of lung: (1) The tumor can be pure hepatoid adenocarcinoma or have components of typical acinar or papillary adenocarcinoma, signet-ring cells or neuroendocrine carcinoma; and (2) AFP expression is not mandatory for diagnosis as long as other markers of hepatic differentiation are expressed.

Radical resection is the preferred treatment for early NSCLC, as is HAL. When HAL presents as localized disease, resection for long-term cure is possible[13]. HAL, like other types of lung cancer, requires early detection in order to achieve better results through surgery. Chen et al[14] found that males might exhibit an increased risk of developing HAL and poorer prognosis than females, and surgical resection combined with chemotherapy might prolong the survival of patients with HAL. As summary of the research finding, the survival benefits for patients receiving chemoradiotherapy or chemotherapy alone appeared to be limited, while radical surgery could significantly improve patient prognosis[15]. Targeted therapy is an important method to treat advanced NSCLC, about 50% of cases of conventional adenocarcinoma of lung harbor somatic mutations in genes that encode proteins in the EGFR signaling pathway: KRAS proto-oncogene, GTPase, EGFR, erb-b2 receptor tyrosine kinase 2, erb-b2 receptor tyrosine kinase 4, BRAF and phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha[16].

Of the 42 cases of HAL, only one case exhibited anaplastic lymphoma kinase (ALK) rearrangement[17]. No article has reported patients had EGFR 19 DEL and 21 L858R mutations. We speculated that the reason was that HAL mostly occurred in heavy smoking men, while EGFR mutations mostly occur in non-smoking women. In addition, the incidence rate of HAL was low, and there were fewer cases for gene testing. This problem needs more test cases to confirm. We used NGS to detect 8 genes (ALK, BRAF, EGFR, ERBB2, KRAS, MET, RET, ROS1) recommended by NCCN guidelines in tissues. The patient was a heavy smoking male, and only KRAS A146T mutation was detected. KRAS mutation is a common mutation in lung cancer and also a factor of poor prognosis of NSCLC[18]. In theory, tumors carrying KRAS mutation may be sensitive to MEK or ERK inhibitors. At present, Sotorasib, a drug targeting KRAS-G12C in KRAS mutation, has begun to be used in patients with advanced NSCLC[19], but has not yet been used as a drug targeting KRAS A146T mutation.

There have been a few reports on immunotherapy for HAL, and more evidence is needed to support whether there is a definite effect[20]. For NSCLC patients with EGFR/ALK/ROS1/BRAF/NTRK/ METex14/RET negative, the 2022 NCCN guidelines recommend Pembrolizumab, Nivolumab, Atezolizumab and other single drugs to be used for first-line treatment of advanced non cell lung cancer with positive programmed death 1 (PD-L1) expression (≥ 50%), while the positive PD-L1 expression (1% ≤ 49%) recommend immune + chemotherapy or dual immune combined treatment. The patient's PD-L1 expression was positive (2%), no definite mutation of targeted drug gene was detected, and performance status score was 2 points, the patient received only one course of ICIs treatment and died 3 months later. However, among the cases reported in the previous literature, there were many HAL cases receiving radiotherapy and chemotherapy, and some patients had achieved good results. Haninger et al[12] reported that a patient with stage IV HAL survived for 9 years after radiotherapy and chemotherapy, among which radiotherapy and chemotherapy were important methods to treat unresectable HAL.

There are still shortcomings in this study. Only one HAL patient was included in this study and died after 3 months of treatment. Not enough information was collected. We will collect more patients and conduct in-depth analysis in future studies.

CONCLUSION

To sum up, HAL is a special type of NSCLC, which is mainly seen in men who smoke heavily. It usually occurs in the upper lobes of both lungs, showing huge masses. The surgical treatment of HAL in the limited period can achieve long-term survival, but most of them are in the advanced stage when they are found, and the prognosis is poor, requiring multidisciplinary comprehensive treatment.